The antidepressant- and anxiolytic-like effects of resveratrol: Involvement of phosphodiesterase-4D inhibition

Zhu, Xia; Li, Wenhua; Xu, Wenhua; Yuan, Yirong; Zheng, Victor; Zhang, Hanting; O’Donnell, James M.; Xu, Ying; Yin, Xiaoxing

doi:10.1016/j.neuropharm.2019.04.022

Cited by 41 publications

(27 citation statements)

References 47 publications

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“…Furthermore, it is important to consider the colocalization of proteins which are proposed to act in concert to respond to the activation of AMPK and other upstream signaling cascades. Related to the potential actions of resveratrol in neurons, more recent studies suggest that phosphodiesterase IV (PDE4) is a putative target for resveratrol, with resveratrolmediated PDE4 inhibition causing an increase in PKA activity, increased availability of cAMP, and increased PGC-1α activity/expression [305][306][307][308][309]. Interestingly, rolipram, a potent inhibitor of PDE4, shows antidepressant effects in humans [310] and neuroprotective efficacy in the quinolinic acid [311] and R6/2 models of HD [160,312].…”

Section: Stimulating Increases In Endogenous Expression Of Pgc-1α Andmentioning

confidence: 99%

Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities

McMeekin

Fox

Boas

et al. 2021

Cells

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Substantial evidence indicates that mitochondrial impairment contributes to neuronal dysfunction and vulnerability in disease states, leading investigators to propose that the enhancement of mitochondrial function should be considered a strategy for neuroprotection. However, multiple attempts to improve mitochondrial function have failed to impact disease progression, suggesting that the biology underlying the normal regulation of mitochondrial pathways in neurons, and its dysfunction in disease, is more complex than initially thought. Here, we present the proteins and associated pathways involved in the transcriptional regulation of nuclear-encoded genes for mitochondrial function, with a focus on the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α). We highlight PGC-1α’s roles in neuronal and non-neuronal cell types and discuss evidence for the dysregulation of PGC-1α-dependent pathways in Huntington’s Disease, Parkinson’s Disease, and developmental disorders, emphasizing the relationship between disease-specific cellular vulnerability and cell-type-specific patterns of PGC-1α expression. Finally, we discuss the challenges inherent to therapeutic targeting of PGC-1α-related transcriptional programs, considering the roles for neuron-enriched transcriptional coactivators in co-regulating mitochondrial and synaptic genes. This information will provide novel insights into the unique aspects of transcriptional regulation of mitochondrial function in neurons and the opportunities for therapeutic targeting of transcriptional pathways for neuroprotection.

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Section: Stimulating Increases In Endogenous Expression Of Pgc-1α Andmentioning

confidence: 99%

Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities

McMeekin

Fox

Boas

et al. 2021

Cells

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“…Activation of this pathway seems to be particularly relevant as genetic deletion of SIRT1, either ubiquitously [113] or specifically in the nucleus accumbens [114] modulates anxiety-like behaviors in mice. A few preclinical studies suggest that resveratrol, a polyphenolic compound that among other actions has been reported to activate SIRT1, may also exert anti-anxiety effects [115,116].…”

Section: Drugs Targeting Mitochondrial Function and Oxidative Stress mentioning

confidence: 99%

Anxiety and Brain Mitochondria: A Bidirectional Crosstalk

Filiou

Sandi

2019

Trends in Neurosciences

116

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Accumulating data highlight the contribution of brain mitochondria and bioenergetics to psychiatric disorders and stress-related pathologies. Although anxiety has not received much attention in this booming literature, a bidirectional interplay between anxiety and brain mitochondria and metabolism has recently started to emerge. Substantial observations indicate alterations in mitochondria and metabolism in highly anxious individuals and, conversely, anxiety symptoms in humans suffering from mitochondrial disorders. Genetic and pharmacological efforts have made substantial progress at advancing the causal involvement of specific mitochondrial and metabolic factors in anxiety. In this review, we discuss this converging evidence and highlight the relevance to develop a research focus on targeting mitochondria as a promising approach to alleviate anxiety.

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“…Studies in mice have placed PDE4D downstream from the calcium influx through the N -methyl-D-aspartate receptor in a pathway that leads to activation of calcium/calmodulin adenylate cyclase and phosphorylation of the cAMP-response element binding protein (CREB) transcription factor (Bailey et al, 1996; Kandel, 2009; Zhang et al, 2018). PDE4D is expressed in layer II/III cortical pyramidal neurons (Cherry and Davis, 1999), which play an important role in major mental disorders including fragile X syndrome, autism, and depression (Sinha et al, 2019; Zamarbide et al, 2019; Zhu et al, 2019). Furthermore, pharmacological inhibition or genetic knockdown of PDE4D activity promotes spine maturation in healthy adult mice and in a genetic model of fragile X syndrome (Gurney et al, 2017; Baumgärtel et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Protection from AmyloidβPeptide–Induced Memory, Biochemical, and Morphological Deficits by a Phosphodiesterase-4D Allosteric Inhibitor

Cui

Zhang

Zheng

et al. 2019

J Pharmacol Exp Ther

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Recent imaging studies of amyloid and tau in cognitively normal elderly subjects imply that Alzheimer's pathology can be tolerated by the brain to some extent due to compensatory mechanisms operating at the cellular and synaptic levels. The present study investigated the effects of an allosteric inhibitor of phosphodiesterase-4D (PDE4D), known as BPN14770 (2-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetic Acid), on impairment of memory, dendritic structure, and synaptic proteins induced by bilateral microinjection of oligomeric amyloid beta (Ab 1-42 into the hippocampus of humanized PDE4D (hPDE4D) mice. The hPDE4D mice provide a unique and powerful genetic tool for assessing PDE4D target engagement. Behavioral studies showed that treatment with BPN14770 significantly improved memory acquisition and retrieval in the Morris water maze test and the percentage of alternations in the Y-maze test in the model of Ab impairment. Microinjection of oligomeric Ab 1-42 caused decreases in the number of dendrites, dendritic length, and spine density of pyramid neurons in the hippocampus. These changes were prevented by BPN14770 in a dose-dependent manner. Furthermore, molecular studies showed that BPN14770 prevented Ab-induced decreases in synaptophysin, postsynaptic density protein 95, phosphorylated cAMP-response element binding protein (CREB)/CREB, brainderived neurotrophic factor, and nerve growth factor inducible protein levels in the hippocampus. The protective effects of BPN14770 against Ab-induced memory deficits, synaptic damage, and the alteration in the cAMP-meditated cell signaling cascade were blocked by H-89 (N-[2-(p-Bromocinnamylamino) ethyl]-5-isoquinolinesulfonamide dihydrochloride), an inhibitor of protein kinase A. These results suggest that BPN14770 may activate compensatory mechanisms that support synaptic health even with the onset of amyloid pathology in Alzheimer's disease. SIGNIFICANCE STATEMENT This study demonstrates that a phosphodiesterase-4D allosteric inhibitor, BPN14770, protects against memory loss and neuronal atrophy induced by oligomeric Ab 1-42. The study provides useful insight into the potential role of compensatory mechanisms in Alzheimer's disease in a model of oligomeric Ab 1-42 neurotoxicity.

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The antidepressant- and anxiolytic-like effects of resveratrol: Involvement of phosphodiesterase-4D inhibition

Cited by 41 publications

References 47 publications

Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities

Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities

Anxiety and Brain Mitochondria: A Bidirectional Crosstalk

Protection from AmyloidβPeptide–Induced Memory, Biochemical, and Morphological Deficits by a Phosphodiesterase-4D Allosteric Inhibitor

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